Heretofore, treatment and management of diabetes has been undertaken through many and varied techniques. Formerly, glucose in urine was measured, though recognized as less than adequate due to the time delay inherent in the metabolism and voiding process. Currently, the approach predominantly used for self- monitoring of blood glucose requires periodic pricks of the skin with a needle, whereby a blood sample is obtained and tested directly to provide information about blood glucose levels. This information is then utilized as a basis from which to schedule the administration of insulin to maintain glucose equilibrium within the patient. Direct measurement of glucose levels in periodic blood samples from diabetes patients provides reasonably useful information about insulin levels at certain selected points in time. However, the dynamic nature of blood glucose chemistry and the complexity of factors influencing blood sugar levels renders such periodic information less than optimal.
The glucose level in the subcutaneous interstitial fluid very closely approximates the glucose level in the blood, with a negligible time lag. The variables of patient food selection, physical activity and insulin dosage, regime and protocol for a person with diabetes each have a dynamic impact on physiologic balance within the patient's body that can change dramatically over a short period of time. If the net result of changes in these variables and dynamics results in disequilibrium expressed as too much glucose (“hyperglycemia”), then more insulin is required, whereas too little glucose (“hypoglycemia”) requires immediate intervention to raise the glucose levels. A deleterious impact on physiology follows either such disequilibrium.
Hyperglycemia is the source of most of the long-term consequences of diabetes, such as blindness, nerve degeneration, and kidney failure. Hypoglycemia, on the other hand, poses the more serious short-term danger. Hypoglycemia can occur at any time of the day or night and can cause the patient to lose consciousness. Guarding against hypoglycemia may require frequent monitoring of blood glucose levels and render the skin-prick approach tedious, painful and in some cases impractical. Even diligent patients who perform finger-sticking procedures many times each day achieve only a poor approximation of continuous monitoring. Accordingly, extensive attention has been given to development of improved means of monitoring patient glucose levels for treatment of diabetes.
Many efforts to continuously monitor glucose levels have involved implantable electrochemical biosensors. These amperometric sensors utilize an immobilized form of the enzyme glucose oxidase to catalyze the conversion of oxygen and glucose to gluconic acid and hydrogen peroxide. Such sensors may be used to measure hydrogen peroxide resulting from the enzymatic reaction. Alternatively, these glucose oxidase based biosensors measure oxygen consumption to infer glucose concentrations.
Typical implantable, subcutaneous needle-type biosensors are disclosed in various publications, such as the following examples. An Amperometric Needle-type Glucose Sensor Tested in Rats and Man, by D. R. Matthews, E. Bown, T. W. Beck, E. Plotkin, L. Lock, E. Gosden, and M. Wickham discloses an amperometric glucose-measuring 25 gauge (0.5 mm diameter) needle-type sensor using a glucose oxidase and dimethyl ferrocene paste behind a semi-permeable membrane situated over a window in the needle. Performance of Subcutaneously Implanted Needle-Type Glucose Sensors Employing a Novel Trilayer Coating, by Francis Moussy, D. Jed Harrison, Darryl W. O'Brien, and Ray V. Rajotte teaches a miniature, needle-type glucose sensor utilizing a perfluorinated ionomer, Nafion, as a protective, biocompatible, outer coating, and poly (o-phenylenediamine) as an inner coating to reduce interference by small, electroactive compounds. Glucose oxidase immobilized in a bovine serum albumin matrix was sandwiched between these coatings. The entire assembly of Pt working electrode and Ag/AgCl reference electrode was 0.5 mm in diameter and could be inserted subcutaneously through an 18-gauge needle. Needle Enzyme Electrodes for Biological Studies by S. J. Churchouse, C. M. Battersby, W. H. Mullen and P. M. Vadgama presents yet another needle enzyme electrode characterized as the most promising approach to miniaturization for invasive use. A Miniaturized Nafion-based Glucose Sensor by F. Moussy, D. J. Harrison, and R. V. Rajotte, while teaching a high sensitivity (due in part to greater surface area of the electrode) needle-type sensor with a spear-shaped point, acknowledges the need for more protection against abrasion. Design and In Vitro Studies of a Needle-Type Glucose Sensor for Subcutaneous Monitoring by Dilbir S. Bindra, Yanan Zhang, George S. Wilson, Robert Sternberg, Daniel R. Thevenot, Dinah Moatti and Gerard Reach sets forth yet another needle-type glucose microsensor having a 26-gauge (0.45-mm) outside diameter.
Additional needle-type implantable biosensors are disclosed in certain United States patent documents. Relevant documents include: “Subcutaneous Glucose Electrode” to Heller et al., U.S. Pat. No. 6,329,161 B1; “Subcutaneous Implantable Sensor Set Having The Capability To Remove Deliver Fluids To An Insertion Site” to Mastrototaro et al., U.S. Pat. No. 5,951,521; “Transcutaneous Sensor Insertion Set” to Halili et al., U.S. Pat. No. 5,586,553; “Transcutaneous Sensor Insertion Set” to Cheney, II et al., U.S. Pat. No. 5,568,806; “Transcutaneous Sensor Insertion Set” to Lord et. al., U.S. Pat. No. 5,390,671; and “Implantable Glucose Sensor” to Wilson et al., U.S. Pat. No. 5,165,407.
To provide continuous measurement, biosensors can be placed for extended periods of time in various locations within the body. One method of placement is percutaneously with an indwelling sensor having an attached external wire associated with a readout device. A risk of infection is associated with percutaneous biosensors, and they must typically be replaced at regular intervals because of the risk of infection at the insertion site.
Another problem with implanted sensors is irritation of the tissues surrounding the implanted biosensors. Such irritation is typically due, in part, to the lateral rigidity of prior art biosensors. Related to this problem is the scarring of surrounding tissue due not only to rigidity but also to abrupt edges associated with the implants. Scar tissue surrounding reference electrodes of the prior art is not desirable, but may be tolerated in some cases. However, scar tissue can be materially detrimental to the sensor function in the vicinity of the working electrode because it impedes the diffusion of oxygen and glucose.
Further, to protect itself against a perceived invader, the body commonly experiences a foreign body reaction by encapsulating the implanted biosensors with protein, which may shorten the life of the implant and adversely affect the accuracy of information provided. The size of the sensor may also be regarded as a problem; smaller is better for comfort. Further yet, interfering compounds, such as for example, ascorbic acid, and acetaminophen, can reduce the accuracy of prior art amperometric glucose sensors given the membranes selected historically to envelope such sensors. Additionally the quantity of dissolved oxygen is limited at high glucose concentrations thus leading to non-linear output of sensor signals at high glucose concentrations.
A need remains for a sensor including a miniaturized probe of suitable materials and characteristics that may facilely be placed percutaneously. A need exists for a miniaturized, albeit durable, implantable biosensor percutaneously deployable wherein irritation to tissues surrounding the biosensor is minimized. A need also exists to achieve a rough exterior of the portion of an implantable biosensor exposed to surrounding tissue so that foreign body reaction may reduced. Similarly, there is a need for a selected membrane or membrane combination suitable to correction of non-linear diffusion of glucose. Further needed is a method of manufacturing such a miniaturized yet strong and durable implantable biosensor with resilient flexibility and minimal surface relief while achieving a microscopically porous surface.